Pharmacokinetics of valproate in pregnancy: mother-foetus-newborn

An increased risk of seizures during and immediately after labour has been observed in epileptic women, and it is recognized that serum levels of antiepileptic drugs may decrease in pregnancy. Several studies have suggested that total valproate levels fall, but that free fractions increase during pregnancy. Recent findings suggest that the actual metabolism of valproate is not altered by pregnancy and that the changes of the plasma clearance are due primarily to decreased protein binding. The levels of free drug will not change significantly as pregnancy advances. However, dose reduction after delivery may be necessary to avoid toxicity. Valproate and its metabolites undergo placental transfer. In the foetus the plasma level of valproate and the protein binding are higher than in maternal plasma, and the half-life of valproate following placental transfer is considerably longer than in adults. Only small amounts of valproate appear in breast milk and those are not likely to cause any problems. During pregnancy and the first month after delivery preferably both total and free valproate serum levels should be closely monitored to determine the lowest effective dose.